This proposal seeks to examine the contribution of oral infection to the morbidity and mortality of cardiovascular disease include atherosclerosis, coronary heart disease (CHD), stroke and myocardial infarction. Newly reported data based upon prospective studies of cardiovascular risk in communities conducted over the last two decades have indicated that prevalent oral infections, and especially periodontitis, are significant risk factors for fatal CHD, and stroke (odds ratio 1.9-2.8), even after controlling for an extensive array of traditional cardiovascular risk factors, such as serum triglyceride, cholesterol, body mass, blood pressure and smoking. The underlying mechanism for this association is unknown and represents the key focus of this proposed investigation. Specifically, we request support to measure serum antibody titers to specific oral microbial pathogens and quantitate the levels of these microbes in oral subgingival plaque samples, collected from a previously characterized population of 14,000 students, to establish whether the presence or levels of specific periodontal pathogens or systemic exposure are associated with cardiovascular disease. This will be a case-control study of subjects with periodontitis who have cardiovascular disease (cases) or no cardiovascular disease (controls). Analyses will be performed on an estimated 1100 periodontitis patients of which 200-300 will be cases. We will test the hypothesis that 4 key pathogens (Porphyromonas gingival, Bacteroides forsythus, Treponema denticola and Actinobacillus actinomycetemcomitans) are significantly associated with CHD case status. We will also screen against a battery or oral organisms including Streptococcus species, known to induce platelet aggregation, to determine whether other microbes are associated with case status. Thus, we are bringing this application forward to request support to enable us to determine from a classic infectious disease standpoint whether specific periodontal pathogens are associated with CHD, in the presence of an unprecedented full complement of cardiovascular risk factors and potential confounders.